Fostriecin (or FST) is a polyketide with phosphate compound inititally separated (1983) from soil bacteria, Streptomyces pulveraceus. Fostriecin was also successfully synthesized via total synthesis by the research group of Boger in 2001. Meanwhile, other compounds (PD113270 and PD113271) with similar structure were also separated and detected in the natural FST producing strains having the structural formula below (see Lewy et. al., 2002).
The in vitro activity of FST on tumor cells such as leukaemia, lung cancer, breast cancer
and ovarian cancer is well-known in the art (leukaemia cells L1210, IC50=0.46 mM), FST is also effective in anti-tumors in vivo. Generally speaking, the activitiy of FST in anti-tumor is due to the selective inhibition on protein phophatase PP2A (IC50=1.5 nM) and PP4 (IC50=3 nM). It has been reported that the chemical synthetic and the naturally occurring FST analogues possess similar activities. For details of FST and analogues thereof, by reference, see Lewy et. al., 2002, “Fostriecin: Chemistry and Biology” Current Medicinal Chemistry 9: 2005-2032. Phase I of the clinical test for FST was stopped due to the difficulty in controlling the chemical purity of the products among different batches and the relatively low stability of the compounds both in vitro and in vivo (e.g. the dephosphation of FST results in the inactivated dephosphorylated FST). Development of FST derivatives of high purity, especially of high stability is highly required.
FST is a weak inhibitor against topoisomerase II (IC50=50 mM), which, however, is the most powerful selective PP2A and PP4 inhibitor. Since some other protein phophatase inhibitors such as okadaic acid and calyculin A generally exhibit the tumor-promoting activity rather than the anti-tumor activity, people are interested in the correlation of the anti-tumor activity of FST with its enzymatic inhibitory activity. In addition, it should be noted that FST can promote the compaction of chromatin, and render the tumor cells sensitive to radiotherapy. Therefore, in order to obtain an effective therapeutic approach in treating tumors or other diseases, development of a series of novel FST analogues either for single administration or combinatory administration is highly required. If it is possible to prepare some FST derivatives with higher stability, such kind of compounds must be clinically more effective, and hence, become a more effective means for treating cancers and are promising to become a novel anti-tumor drug having a novel mechansium of action.